L-Pipecolic acid is important as a raw material for the synthesis of drugs. At present, L-pipecolic acid is being produced by synthesis from L-lysine (J. Chem. Soc. Chem. Commun., 1985, pp. 633–635) or by the optical resolution of DL-pipecolic acid prepared by synthesis from picolinic acid (Method of Enzymol., 17B, pp. 174–188, 1971). As methods for optical resolution, there are known a diastereomer salt method using D-tartaric acid and an enzymatic method in which D-amino acid oxidase derived from pig liver is used to decompose the D-isomer while leaving the L-isomer.
On the other hand, it is known that L-pipecolic acid is produced in animals (J. Biol. Chem., Vol. 211, p. 851, 1954), plants (J. Amer. Chem. Soc., Vol. 74, p. 2949, 1952) and microorganisms (Biochemistry, Vol. 1, pp. 606–612, 1926; Japanese Patent Laid-Open No. 38781/'94). However, since the amount of L-pipecolic acid accumulated therein is small, no process for the production of L-pipecolic acid by using these organisms has been put to practical use. From previous investigations on the metabolism of L-lysine, it is known that delta-1-piperideine-6-carboxylic acid (hereinafter also referred to as P6C) is formed from L-lysine through a transamination reaction by lysine 6-aminotransferase (hereinafter also referred to as LAT) (Biochemistry, Vol. 7, pp. 4102–4109, 1968) or by the action of L-lysine 6-dehydrogenase (J. Biochem., Vol. 105, pp. 1002–1008, 1989).
It has been reported P6C can be chemically converted into L-pipecolic acid by hydrogenation using platinum oxide (Biochemistry, Vol. 7, pp. 4102–4109, 1968), but there is no report about the formation of L-pipecolic acid by the biological or enzymatic reduction of P6C. Moreover, a metabolic pathway is supposed in which Pseudomonas putida produces L-pipecolic acid from D-lysine via delta-1-piperideine-2-carboxylic acid. It is also difficult to utilize such biological pathways for the mass production of L-pipecolic acid.
In the above-described process involving the optical resolution of DL-pipecolic acid prepared by chemical synthesis, the optical resolving agent used is expensive and a complicated procedure is required. Moreover, in the process using an enzyme for purposes of optical resolution, the use of a purified enzyme is also expensive. Because of these disadvantages, both processes are not efficient from an industrial point of view and cannot produce L-pipecolic acid cheaply.
Furthermore, conventional processes for the production of L-pipecolic acid by using microorganisms have not been put to practical use because the amount of L-pipecolic acid accumulated is small.